3-Methylpyrazole-5-carboxylates and medicaments containing these compounds

ABSTRACT

This invention relates to 3-methylpyrazole-5-carboxylates, to processes for the preparation of said compounds and to pharmaceutical compositions containing said compounds.

This invention relates to 3-methylpyrazole-5-carboxylates correspondingto the general formula: ##SPC1##

In which R₁ and R₂ each represent hydrogen, straight-chain or branchedalkyl radicals with 1 to 4 carbon atoms, hydroxyalkyl, alkoxyalkyl,aralkyl or norbornyl groups or, together with the nitrogen atom to whichthey are attached, represent a morpholine radical.

The compounds according to the invention are obtained by reactingcorrespondingly substituted 1,3-dimethylxanthines corresponding to thegeneral formula: ##SPC2##

In which R₁ and R₂ are as defined above, with3-methylpyrazole-5-carboxylic acid, preferably in equimolar quantities,in the presence of a solvent.

The reaction is best carried out at a temperature in the range from 40°to 100°C, preferably at the boiling temperature of the solvent.

Suitable solvents are, primarily, lower alcohols such as methanol,ethanol, isopropanol and the various butanols, to which other solvents,such as ethyl acetate, water, etc. may optionally be added in smallquantities in order to improve the crystallisability of the claimedcompounds.

The theophylline bases of general formula II used for preparation of thecompounds of general formula I are employed in pure form or, ifpurification is not possible, in the form of crude products.

The resulting compounds of formula I are preferably recrystallised fromlower alcohols, for example methanol, ethanol, propanol, isopropanol andthe various butanols, optionally by the addition of other solvents, suchas water, ethyl acetate, acetone, dioxan, or alternatively mixtures ofdifferent solvents are used.

The compounds produced in accordance with the invention aredistinguished by their pronounced lipolysis-inhibiting activity, theireffectiveness in reducing triglyceride and cholesterol level and theirlow toxicity.7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-carboxylatehas a particularly marked effect.

Hyperlipidaemiae are a serious health risk because they promote thedevelopment of arteriosclerosis to a considerable extent. Accordingly,preparations which reduce lipid level, i.e. which reduce the content oftriglycerides, free fatty acids and cholesterol in the blood serum, areof considerable importance.

It is known per se that the free 3-methylpyrazole-5-carboxylic acidshows corresponding activity.

When feeding 3-methylpyrazole-5-carboxylic acids to starving rats, DavidL. Smith et al (J. Med. Chem. 8 (3), 350-3 (1965)) found that thiscompound exceed the hypoglycaemic activity of tolbutamide(N-butyl-N'-toluene-p-sulphonylurea) by two hundred times.

It has been reported from other sources (G. Gerritzen et al, Advan. Exp.Med. Biol. (1969) 4, 93-103 and G. Tamasi et al, Med. Pharmacol. Exp. 16(1967) 6, 573-8) that, when administered in small doses to starvingnormal rats, this substance reduces the level of free fatty acids andtriglycerides in the serum. However, the tachyphylaxia of thissubstance, as observed by the authors, limits its suitability fortherapeutic application.

Surprisingly, however, the derivatives according to the invention,derived from the base theophylline, have no tachyphylactic propertiesdespite their particularly pronounced lipolysis-inhibiting effect.

The invention is illustrated by the following Examples.

EXAMPLE 17-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-carboxylate

8.6 g (0.0276 mol) of7-[3-(N-methyl-N-2-hydroxyethyl)amino-2-hydroxypropyl]-1,3-dimethylxanthine(TLC-pure) are dissolved in 30 ml of absolute ethanol, followed by thedropwise addition with stirring (magnetic stirrer) at boilingtemperature of a solution of 3.5 g (0.0276 mol) of3-methylpyrazole-5-carboxylic acid (TLC-pure) in 100 ml of absoluteethanol.

On completion of the addition, the clear solution is allowed to cool toroom temperature. Colourless crystals precipitate after a while, beingfiltered off under suction.

Another crystal fraction is obtained from the mother liquor concentratedin vacuo by leaving it standing in a refrigerator. This additionalcrystal fraction is combined with the first and recrystallised fromethanol. The salt thus obtained melts at 161.5 to 162.5°C.

Total yield: 10.2 g = 84% of the theoretical

    ______________________________________                                        Analysis:                                                                              C         H         N       O                                        ______________________________________                                        Calc.:   49.42     6.22      21.95   22.41                                    Found:   49.97     6.24      21.68   22.05                                    ______________________________________                                    

EXAMPLES 2 to 12

The other compounds of general formula I listed in Table I were producedin accordance with Example 1.

                                      T a b l e I                                 __________________________________________________________________________                                           Yield                                                               Melting point in °C                                                              in % of                                Exp.                         solvent for re-                                                                         theo-                                                                             Combustion analysis                No.                                                                              R.sub.1    R.sub.2        crystallisation                                                                         retical C   H   N   O                  __________________________________________________________________________    1  --CH.sub.3 --CH.sub.2 --CH.sub.2 --OH                                                                   161.5-162.5                                                                             84  Calc.:                                                                            49.42                                                                             6.22                                                                              21.95                                                                             22.41                                           ethanol       Found:                                                                            49.97                                                                             6.24                                                                              21.68                                                                             22.05              2  H                         195-197   45  Calc.:                                                                            55.69                                                                             6.80                                                                              20.66                                                                             16.86                                           ethyl acetate/                                                                              Found:                                                                            55.95                                                                             6.77                                                                              19.90                                                                             17.22                                           petrol 100-40                                    3  H          --CH.sub.2 --CH.sub.2 --OH                                                                   212.5-214 91  Calc.:                                                                            48.22                                                                             5.95                                                                              23.11                                                                             22.64                                           aqueous ethanol/                                                                            Found:                                                                            48.04                                                                             5.92                                                                              23.06                                                                             22.96                                           ethyl acetate                                    4  H          CH.sub.3       157-159   70  Calc.:                                                                            51.60                                                                             6.72                                                                              21.06                                                                             20.62                            |     ethanol       Found:                                                                            51.65                                                                             6.80                                                                              20.96                                                                             20.70                            --C--CH.sub.2 --CH.sub.2 --OH                                                 |                                                                    CH.sub.3                                                        5  H          --CH.sub.2 --CH.sub.2 --O-- C.sub.2 H.sub.5                                                  139-141   74  Calc.:                                                                            50.54                                                                             6.48                                                                              21.72                                                                             21.26                                           ethanol       Found:                                                                            50.69                                                                             6.38                                                                              22.20                                                                             20.70              6  H          --CH.sub.2 --CH.sub.2 --CH.sub.2 --OC.sub.2 H.sub.                                           193-193.5 57  Calc.:                                                                            51.61                                                                             6.71                                                                              21.06                                                                             20.62                                           ethyl acetate/                                                                              Found:                                                                            52.14                                                                             6.81                                                                              20.85                                                                             20.16                                           ethanol                                          7  H          --CH.sub.2 --CH.sub.2                                                                        215.216.5 86  Calc.:                                                                            57.14                                                                             6.04                                                                              20.28                                                                             16.55                                           ethyl acetate/                                                                              Found:                                                                            57.08                                                                             6.18                                                                              19.71                                                                             16.99                                           ethanol                                          8  H          CH.sub.3       151-152   68  Calc.:                                                                            53.44                                                                             6.95                                                                              21.81                                                                             17.80                            |     dioxan/       Found:                                                                            53.40                                                                             6.91                                                                              21.52                                                                             18.20                            --C--CH.sub.2 --CH.sub.3                                                                     petroleum ether                                                |                                                                    CH.sub.3                                                        9  --CH.sub.2 --CH.sub.3                                                                    --CH.sub.2 --CH.sub. 3                                                                       167.0-168.5                                                                             82  Calc.:                                                                            52.40                                                                             6.71                                                                              22.51                                                                             18.37                                           isopropanol   Found:                                                                            52.51                                                                             6.61                                                                              22.56                                                                             18.49              10 --CH.sub.2 --CH.sub.2 CH.sub.3                                                                          98-99                                                                         ethyl acetate/ethanol                                                                   73  Calc.:                                                                            57.26                                                                             7.41                                                                              19.47                                                                             15.88                                                         Found:                                                                            57.09                                                                             7.67                                                                              18.78                                                                             16.56              11 --CH.sub.2 --(CH.sub.2).sub.2 --CH.sub.3                                                                95.5-97   43  Calc.:                                                                            58.02                                                                             7.60                                                                              18.94                                                                             15.45                                           ethanol       Found:                                                                            57.21                                                                             7.76                                                                              18.96                                                                             15.94              12                           224-225   58  Calc.:                                                                            50.77                                                                             6.06                                                                              21.81                                                                             21.35                 O                                       Found:                                                                            50.67                                                                             6.06                                                                              21.64                                                                             21.61              __________________________________________________________________________

PHARMACOLOGICAL INVESTIGATIONS

Investigations on a total of 260 Wistarrats were conducted with7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-carboxylate.This compound significantly influences the free fatty acids (FFS) afterthe application of doses down to 2 mg/kg body weight both in normalanimals and in hyperlipacidaemic animals (starved animals, alcoholanimals). The lypolysis-inhibiting effect is more pronounced than thatof the free 3-methylpyrazole-5-carboxylic acid, which was found incomparative examinations with equimolar dosage and which was reflectedin different significance limits especially 6 hours after application.

It was also found that the compound7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-carboxylatesignificantly reduces the cholesterol level of starved rats whenadministered perorally in a dose of 100 mg/kg of body weight.

In doses of down to 10 mg/kg of body weight, it also significantlyreduces the serum triglyceride level of normal animals. By contrast,equimolecular doses of the free acid produce only a relatively weak,i.e. insignificant effect.

In hyperlipacidaemic rats treated with octylphenol polyethyleneglycolether, the above-mentioned compound according to the inventionproduces a significant reduction in the triglyceride level.

After the repeated application of 100 mg/kg of body weight over a periodof 4 days, the compound showed a uniform and, in some cases, evenincreased effect on the serum triglycerides and the serum cholesterol.

Even on the fourth day, both parameters were still significantlyreduced.

It is known from the works of Gerritzen et al that pretreatment of thetest animals for 4 to 5 days with 3-methylpyrazole-5-carboxylic acidweakens the effect on the free fatty acid content of the plasma. We wereable to confirm the results of these tests. However, we found that thecomound7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-carboxylatedoes not have this effect.

The results of our tests are shown in Table 13 and FIG. 4.

The results are shown in Tables 1 to 13 and in FIGS. 1 to 4.

The LD₅₀ of the compound in mice amounts to more than 1000 mg/kg peroral and to 540 mg/kg i.v.

The other compounds according to the invention show equally pronouncedpharmacological effects.

                  TABLE 1                                                         ______________________________________                                        Examination of the influence of 7-[3-(N-methyl-N-2-hydroxy-                   ethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methyl-                  pyrazole-5-carboxylate on the serum fatty acids (FFS) of                      normal animals                                                                Test arrangement:                                                             Female rats, starve for 5 hours                                               Dose: 100 mg/kg body weight, oral by esophagus probe,                         Blood removal: 1 hour after application                                       FFS                                                                           ______________________________________                                        Animal No.                                                                             Weight/g μval/ml                                                  1        199      0.56                                                        2        179      0.54     CONTROL                                            3        218      0.62     (H.sub.2 O esophagus probe)                        4        142      0.63                                                        5        214      0.56                                                        6        197      0.51                                                        7        216      0.54                                                        8        195      0.59                                                        9        213      0.65                                                        10       199      0.78     φ 0.60 μval/ml                              ______________________________________                                        1        200      0.51                                                        2        186      0.58                                                        3        219      0.52     TEST SERIES                                        4        194      0.56                                                        5        198      0.51                                                        6        204      0.57                                                        7        215      0.48                                                        8        198      0.54     φ 0.53 μval/ml                              ______________________________________                                    

                  Table 2                                                         ______________________________________                                        Examination of the influence of 7-[3-(N-methyl-N-2-hydroxy-                   ethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methyl-                  pyrazole-5-carboxylate on the serum fatty acids (FFS) of                      hyperlipacidaemic rats                                                        Test arrangement:                                                                              a) Hunger lipolysis                                          Male Rats, starve for 17 hours                                                Dose: 100 mg/kg body weight, oral by esophagus probe,                         Blood removal: 1 hour after application                                       ______________________________________                                                          FFS                                                         Animal No.                                                                             Weight/g μval/ml                                                  1        162      0.52                                                        2        197      0.81                                                        3        181      1.10                                                        4        195      1.03                                                        5        145      0.79     CONTROL                                            6        140      0.76     (H.sub.2 O-esophagus probe)                        7        140      1.30                                                        8        147      0.65                                                        9        146      1.06                                                        10       157      0.79     φ 160 g BW/0.91 μval/ml                     11       165      0.95                                                        12       155      0.92                                                        13       158      1.09                                                        14       159      0.99                                                        15       148      0.94                                                        ______________________________________                                        1        208      0.29                                                        2        178      0.34                                                        3        173      0.54                                                        4        189      0.47     TEST SERIES                                        5        144      0.67                                                        6        140      0.46                                                        7        148      0.44                                                        8        144      0.43                                                        9        146      0.39                                                        10       148      0.47     φ 160 g BW/0.46 μval/ml                     11       158      0.48     p<0.001                                            12       154      0.51                                                        13       162      0.47                                                        14       158      0.45                                                        15       152      0.51                                                        ______________________________________                                    

                  Table 3                                                         ______________________________________                                        Examination of the influence of 7-[3-(N-methyl-N-2-hydroxy-                   ethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methyl-                  pyrazole-5-carboxylate on the serum fatty acids (FFS) of                      hyperlipacidaemic rats                                                        b) Alcohol lipolysis                                                          Test arrangement:                                                             rats, starve for 5 hours,                                                     Dose: alcohol 2g/kg body weight in 20% solution i.v.,                         Dose: active principle according to the invention                             100 mg/kg body weight, oral by esophagus probe                                3 hours before blood removal                                                  ______________________________________                                                           FFS                                                        Animal No.                                                                             Weight(g) (μval/ml)                                               ______________________________________                                        1        218       0.45                                                       2        206       0.77                                                       3        223       0.50                                                       4        234       0.66      CONTROL                                          5        188       0.73                                                       6        211       0.75      φ 0.64 μval/ml                            7        167       0.62                                                       8        182       0.66                                                       9        160       0.45                                                       10       189       0.81                                                       ______________________________________                                        1        161       0.77                                                       2        181       1.00                                                       3        177       1.06                                                       4        182       0.78      ALCOHOL SERIES                                   5        178       0.85                                                       6        184       0.50      φ 0.79 μval/ml                            7        190       0.74      p<0.05                                           8        169       0.78                                                       9        166       0.73                                                       10       176       0.70                                                       ______________________________________                                        1        150       0.45                                                       2        164       0.58                                                       3        188       0.59      ALCOHOL SERIES +                                 4        178       0.60      active principle                                 5        168       0.52      according to the                                 6        188       0.56      invention                                        7        178       0.43      φ 0.56 μval/ml                            8        170       0.66      p<0.001                                          9        141       0.67                                                       10       165       0.53                                                       ______________________________________                                    

                  Table 4                                                         ______________________________________                                        Examination of the influence of 7-[3-(N-methyl-N-2-hydroxy-                   ethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-methyl-                  pyrazole-5-carboxylate on the free fatty acids (FFS) in                       starved animals 1 hour after application                                      Dose - Effect relations                                                                 7-[3-(N-methyl-N-2-hydroxyethyl)-amino-                                       2-hydroxypropyl]-1,3-dimethylxanthine-                              CONTROL   3-methylpyrazole-5-carboxylate                                      ______________________________________                                        FFS           Dose      FFS                                                   μval/ml                                                                           n      mg/kg     μval/ml                                                                             n                                            ______________________________________                                         0.91* 15     100       0.46*    15    *p<0.001                                1.08**                                                                              10     50        0.40**   10    **p<0.001                              1.02   2      40        0.48     5                                            1.02   2      30        0.54     4                                            0.90   3      20        0.56     5                                            0.97   5      10        0.53     10                                           0.83   3      5         0.43     5                                            0.86   7      2.5       0.50     13                                            0.87**                                                                              10     2.0       0.51***  10   ***p<0.001                              ______________________________________                                    

                  Table 5                                                         ______________________________________                                        Comparative examinations of the influence of 7-[3-(N-methyl-                  N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-                3-methylpyrazole-5-carboxylate and 3-methylpyrazole-5-                        carboxylic acid on the free fatty acids (FFS) in starved                      animals 1 hour after application                                              (cf. FIG. 1)                                                                          7-[3-(N-methyl-N-2-hydroxyethyl)-                                                                   3-methyl-                                               amino-2-hydroxypropyl]-1,3-di-                                                                      pyrazole-                                               methylxanthine-3-methylpyrazole-                                                                    5-carboxylic                                                                  acid                                            CONTROL 5-carboxylate 50 mg/kg                                                                              15 mg/kg                                        FFS     FFS                   FFS                                             μval/ml                                                                            μval/ml            μval/ml                                      ______________________________________                                        0.96    0.39                  0.41                                            1.08    0.44                  0.43                                            1.33    0.46                  0.59                                            1.07    0.40                  0.52                                            1.32    0.35                  0.67                                            0.98    0.45                  0.37                                            1.02    0.37                  0.40                                            1.12    0.32                  0.37                                            0.88    0.39                  0.54                                            0.99    0.41                  0.44                                            .sup.*1.08                                                                            0.40                  0.47                                             n=10   n=10                  n=10                                                    p<0.001               p<0.001                                         ______________________________________                                    

                  Table 6                                                         ______________________________________                                        Comparative examinations of the influence of 7-[3-(N-methyl-                  N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethyl-                        xanthine-3-methylpyrazole-5-carboxylate and 3-methyl-                         pyrazole-5-carboxylic acid on the free fatty acids (FFS)                      in starved animals 6 hours after application                                  (cf. FIG. 1)                                                                          7-[3-(N-methyl-      3-methyl-                                                N-2-hydroxyethyl-    pyrazole-                                                amino-2-hydroxypropyl]                                                                             5-carboxylic                                             1,3-dimethylxanthine-                                                                              acid                                                     3-methylpyrazole-5-carboxylate                                                                     15 mg/kg                                         CONTROL 50 mg/kg BW p.o.     p.o.                                             FFS     FFS                  FFS                                              μval/ml                                                                            μval/ml           μval/ml                                       ______________________________________                                        0.89    0.39                 0.51                                             1.06    0.35                 0.50                                             0.78    0.35                 0.67                                             0.91    0.43                 0.64                                             0.88    0.35                 0.50                                             0.98    0.58                 0.56                                             0.86    0.54                 0.53                                             0.80    0.63                 0.61                                             0.78    0.77                 0.51                                             0.72    0.52                 0.85                                             0.70    0.51                 0.67                                             0.70    0.96                 0.44                                             0.88    0.59                 0.54                                             0.91    0.43                 0.58                                             0.89    0.78                 1.00                                             0.69    0.53                 0.54                                             0.65    0.96                 0.47                                             0.82    0.44                 0.47                                             0.81    0.64                 1.46                                             1.00    0.85                 0.56                                             1.00    0.32                 1.10                                             0.87                                                                          0.70                                                                          0.87                                                                          1.29                                                                          x 0.86  0.57                 0.69                                             n=25    21                   21                                                       p<0.001              p<0.01                                           ______________________________________                                    

                                      Table 7                                     __________________________________________________________________________    Comparative examinations of the influence of 7-[3-(N-methyl-                  N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-                3-methylpyrazole-5-carboxylate and 3-methylpyrazole-5-                        carboxylic acid on the serum triglycerides (TG) in normal animals             cf. FIG. 2                                                                    __________________________________________________________________________    Test arrangement:                                                             Rats, starve for 5 hours                                                      Dose:                                                                              40 mg/kg body weight of active principle according to                         the invention, oral by esophagus probe 1 hour before                          removal of blood                                                         Dose:                                                                              12 mg/kg body weight of 3-methylpyrazole-5-carboxylic                         acid, equim. dosage, 1 hour before removal of blood                      __________________________________________________________________________                 TG                                                               Animal No.                                                                           Weight (g)                                                                          mg %  CONTROL                                                    __________________________________________________________________________    1      154   73.0                                                             2      160   67.3                                                             3      150   71.6  x = 66.4 mg %                                              4      164   48.7                                                             5      171   71.6                                                             1      188   71.6                                                             2      178   22.9  7-[3-(N-methyl-N-2-hydroxy-                                3      188   15.8  ethyl)-amino-2-hydroxy-                                    4      198   15.8  propyl]-1,3-dimethylxanthine-                              5      189   18.6  3-methylpyrazole-5-carboxylate                             6      180   41.5                                                             7      171   40.1  x = 36.3 mg %                                              8      171   58.7  p<0.0027>Ko                                                9      177   32.9                                                             10     161   45.8                                                             1      193   90.2                                                             2      204   87.3  3-methylpyrazole-5-                                        3      185   90.2  carboxylic acid                                            4      200   58.7                                                             5      176   107.4 x = 74.1 mg %                                              6      175   51.6                                                             7      161   55.8                                                             8      161   71.6                                                             9      166   60.1                                                             10     176   68.7                                                             __________________________________________________________________________

                                      Table 8                                     __________________________________________________________________________    Comparative examinations of the influence of 7-[3-(N-methyl-N-2-              hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethylxanthine-3-                  methylpyrazole-5-carboxylate and 3-methylpyrazole-5-carboxylic acid           on the serum triglycerides (TG) in normal animals (cf. FIG. 2)                Test Arrangement:                                                             Rats,starve for 5 hours                                                       Dose: 10 mg/kg body weight of active principle according to the               invention, oral by esophagus probe 1 hour before blood removal                Dose: 3 mg/kg body weight of 3-methylpyrazole-5-carboxylic acid,              equim. dosage, oral by esophagus probe 1 hour before                          blood removal                                                                 __________________________________________________________________________                 TG                                                               Animal No.                                                                           Weight (g)                                                                          mg % CONTROL                                                     __________________________________________________________________________    1      217   105.9                                                            2      227   63.0                                                             3      220   110.3                                                            4      190   60.1                                                             5      200   127.4                                                            6      200   113.1                                                                              x = 86.3 mg %                                               7      211   61.6                                                             8      196   63.0                                                             9      200   98.8                                                             10     207   60.1                                                             1      188   48.7                                                             2      162   54.4 7-[3-(N-methyl-N-2-hydroxyethyl)-                           3      189   83.1 amino-2-hydroxypropyl]-1,3-di-                              4      189   54.4 methylxanthine-3-methylpyrazole-                            5      181   55.8 5-carboxylate                                               6      198   74.4                                                             7      209   81.6 x = 59.8 mg %                                               8      198   51.5 p<0.05>Ko                                                   9      183   54.4                                                             10     183   40.1                                                             1      188   137.4                                                            2      180   87.3                                                             3      168   70.2 3-methylpyrazole-5-                                         4      181   74.4 carboxylic acid                                             5      185   50.1                                                             6      207   43.0 x = 67.7 mg %                                               7      212   57.2 p>0.05→Ko.                                           8      190   51.5 p>0.05→xant.-carbox.                                 9      190   32.9                                                             10     214   73.0                                                             __________________________________________________________________________

                  Table 9                                                         ______________________________________                                        Triglycerides                                                                 Test arrangement:                                                             Male rats, starve for 22 hours, ether narcosis, heart puncture                Dose: 1000 mg/kg of octylphenyl polyethylene glycolether i.v.                 6 hours before blood removal                                                  Dose: 100 mg/kg of 7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-                  hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-                       carboxylate by esophagus probe, 6 hours, 4 hours and                          2 hours before blood removal                                                  ______________________________________                                                Weight                                                                Animal No.                                                                            (g)     TG mg %  CONTROL                                              ______________________________________                                        1       199     746.1                                                         2       200     786.2    Octylphenol polyethylene                             3       178     776.1    glycolether                                          4       194     764.7    1000 mg/kg i.v.                                      5       186     791.9    6 hours before killing                               6       197     764.7                                                         7       216     777.6                                                         8       160     784.7                                                         9       208     794.8                                                         10      176     784.7                                                                         x = 777.2                                                     1       196     644.4    Octylphenol polyethyelene                            2       188     687.4    glycolether                                          3       186     701.6    1000 mg/kg i.v.                                      4       198     707.4    6 hours before killing                               5       209     701.6    +                                                    6       196     610.0    100 mg/kg of 7-[3-(N-methyl-                         7       198     703.1    N-2-hydroxyethyl)-amino-2-                           8       214     695.9    hydroxypropyl]-1,3-dimethyl-                         9       197     711.7    xanthine-3-methylpyrazole-                           10      197     707.4    5-carboxylate per os                                                 x 687.0  6, 4 and 2 hours before                                                       killing                                                                       p<0.001                                              ______________________________________                                    

                                      Table 10                                    __________________________________________________________________________    Assaying for cholesterol                                                      Male Rats, starve for 18 hours, ether narcosis, heart puncture                7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-                                     hydroxypropyl]-1,3-dimethylxanthine-3-                                        methylpyrazole-5-carboxylate                                                  __________________________________________________________________________                     1 hour before killing                                                         100 mg/kg of 7-[3-(N-methyl-N-                                                2-hydroxyethyl)-amino-2-hydroxy-                                              propyl]-1,3-dimethylxanthine-                                                 3-methylpyrazole-5-carboxylate                               Control Animals  per os                                                       __________________________________________________________________________              Cholesterol      Cholesterol                                        No. Weight (g)                                                                          mg %   No. Weight (g)                                                                          mg %                                               __________________________________________________________________________    1   204   90.52  1   219   78.45                                              2   240   76.72  2   152   50.86                                              3   238   82.76  3   198   57.76                                              4   250   79.31  4   196   47.71                                              5   230   65.52  5   203   62.07                                              6   225   74.14  6   178   48.28                                              7   150   62.07  7   190   65.52                                              8   210   67.24  8   200   56.03                                              9   200   78.45  9   200   65.52                                              10  236   80.17  10  224   38.79                                              __________________________________________________________________________    x.sub.10                                                                          218   75.69  x.sub.10                                                                          196   57.07                                                        p<0.001                                                             __________________________________________________________________________

                                      Table 11                                    __________________________________________________________________________    Influence on the serum cholesterol of repeated application of                 7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethyl-         xanthine-3-methylpyrazole-5-carboxylate                                       100 mg/kg x/day p.o. rats male, starve for 5 hours, ether narcosis, heart     puncture,                                                                     last application 1 hour before killing (cf. FIG. 3)                           __________________________________________________________________________    Animal                                                                             Control    1st day    2nd day     3rd day     4th day                    No.  weight                                                                             mg %  weight                                                                             mg %  weight                                                                              mg %  weight                                                                              mg %  weight                                                                             mg                    __________________________________________________________________________                                                            %                     1    180 g                                                                              64.10 177 g                                                                              71.70 270 g 37.4  200 g 52.36 200 g                                                                              42.98                 2    206 g                                                                              69.23 275 g                                                                              49.06 210 g 54.2  190 g 71.24 190 g                                                                              37.19                 3    208 g                                                                              65.82 177 g                                                                              51.89 200 g 55.2  200 g 67.81 170 g                                                                              52.07                 4    220 g                                                                              78.63 198 g                                                                              67.92 210 g 69.9  190 g 50.64 170 g                                                                              64.46                 5    210 g                                                                              70.09 170 g                                                                              51.89 200 g 65.0  180 g 57.51 180 g                                                                              80.99                 6    240 g                                                                              61.54 190 g                                                                              68.87 190 g 69.1  190 g 64.38 170 g                                                                              47.11                 7    210 g                                                                              60.68 178 g                                                                              52.83 270 g 39.4  190 g 62.66 180 g                                                                              65.29                 8    205 g                                                                              76.92 170 g                                                                              52.83 260 g 47.3  200 g 71.24 220 g                                                                              58.68                 9    210 g                                                                              81.20 175 g                                                                              68.87 200 g 49.3  180 g 68.67 170 g                                                                              50.41                 10   204 g                                                                              84.62 150 g                                                                              50.94 150 g 51.2  190 g 60.94 170 g                                                                              43.80                 x.sub.10                                                                           209 g                                                                              71.28 176 g                                                                              58.68 215 g 53.8  191 g 62.75 182 g                                                                              54.30                 __________________________________________________________________________

                                      Table 12                                    __________________________________________________________________________    Influence on the serum triglycerides of repeated application of               7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-hydroxypropyl]-1,3-dimethyl-         xanthine-3-methylpyrazole-5-carboxylate                                       100 mg/kg x/day p.o. rats male, starve for 5 hours, ether narcosis, heart     puncture,                                                                     last application 1 hour before killing (cf. FIG. 3)                           __________________________________________________________________________    Animal                                                                             Control    1st day    2nd day     3rd day     4th day                    No.  weight                                                                             mg%   weight                                                                             mg%   weight                                                                              mg%   weight                                                                              mg%   weight                                                                             mg%                   __________________________________________________________________________    1    180 g                                                                              103.1 177 g                                                                              85.9  270 g 38.7  200 g 60.1  200 g                                                                              30.1                  2    206 g                                                                              141.8 175 g                                                                              57.3  210 g 61.6  190 g 63.0  190 g                                                                              73.0                  3    208 g                                                                              153.2 177 g                                                                              118.6 200 g 54.4  200 g 90.2  170 g                                                                              67.0                  4    220 g                                                                              154.6 198 g                                                                              104.5 210 g 63.0  190 g 108.8 170 g                                                                              64.4                  5    210 g                                                                              126.0 170 g                                                                              65.9  200 g 95.9  180 g 50.1  180 g                                                                              60.1                  6    240 g                                                                              136.0 190 g                                                                              57.3  190 g 87.3  190 g 97.4  170 g                                                                              44.4                  7    210 g                                                                              127.4 178 g                                                                              104.5 270 g 127.4 190 g 60.1  180 g                                                                              44.4                  8    205 g                                                                              115.9 170 g                                                                              85.9  250 g 74.4  200 g 80.2  220 g                                                                              58.7                  9    210 g                                                                              144.6 175 g                                                                              57.3  200 g 57.2  180 g 105.9 170 g                                                                              101.7                 10   204 g                                                                              133.2 150 g                                                                              88.8  150 g 88.7  190 g 58.7  170 g                                                                              67.3                  x.sub.10                                                                           209 g                                                                              133.6 176 g                                                                              82.6  215 g 74.8  191 g 77.4  182 g                                                                              61.1                  __________________________________________________________________________

                                      Table 13                                    __________________________________________________________________________    Influence of 7-[3-(N-methyl-N-2-hydroxyethyl)-amino-2-                        hydroxypropyl]-1,3-dimethylxanthine-3-methylpyrazole-5-carboxylate            on the free fatty acids (FFS)                                                 Rats male, repeated application once daily for 4 days,                        on the 4th day groups of 10 animals were killed at                            intervals of 30 minutes, 1 hour and 2 hours after the                         last application by ether narcosis and heart puncture.                        10 controls were given esophagus probe, animals starved                       for 17 hours before killing (cf. FIG. 4)                                      Preparation:                                                                         7-[3-(N-methyl-2-hydroxyethyl)-amino-2-                                       hydroxypropyl]-1,3-dimethylxanthine-3-                                        methylpyrazole-5-carboxylate 50 mg/kg peroral                                 3-methylpyrazole-5-carboxylic acid (3-MPC)                                    eq./kg 15 mg/kg peroral                                                Method:                                                                              Acta. Biol. Vol. 12, 520 (1964)                                        Animal No.                                                                           Weight (g)                                                                          μval/ml plasma                                                                     CONTROL                                                  __________________________________________________________________________    1      160   1.17                                                             2      210   1.21                                                             3      230   1.24                                                             4      200   1.28                                                             5      230   1.12                                                             6      260   1.41                                                             7      230   1.30                                                             8      240   1.24                                                             9      240   1.49                                                             10     220   1.31                                                             x.sub.10                                                                             222   1.27                                                             1      270   0.72    7-[3-(N-methyl-N-2-                                      2      240   0.94    hydroxyethyl)-amino-2-                                   3      240   0.69    hydroxypropyl]-1,3-                                      4      240   0.83    dimethylxanthine-3-                                      5      230   1.36    methylpyrazole-5-                                        6      230   0.89    carboxylate                                              7      230   0.66    4 × appl. 50 mg/kg p.o.                            8      240   0.67    30' after last application +                             9      240   0.86                                                             10     240   1.07                                                             x.sub.10                                                                             240   0.87    p<0.001                                                  1      230   0.75    7-[3-(N-methyl-N-2-                                      2      200   0.42    hydroxyethyl)-amino-2-                                   3      220   0.45    hydroxypropyl]-1,3-                                      4      220   0.56    dimethylxanthine-3-                                      5      240   0.67    methylpyrazole-5-                                        6      230   0.54    carboxylate                                              7      200   0.86    4 × appl. 50 mg/kg p.o.                            8      230   0.63    1 h after last appl. +                                   9      260   0.98                                                             10     230   0.89                                                             x.sub.10                                                                             226   0.68    p<0.001                                                  1      250   0.79    7-[3-(N-methyl-N-2-                                      2      240   0.58    hydroxyethyl)-amino-2-                                   3      220   0.94    hydroxypropyl]-1,3-                                      4      190   0.80    dimethylxanthine-3-                                      5      190   1.10    methylpyrazole-5-                                        6      240   1.07    carboxylate                                              7      210   0.84    4 × appl. 50 mg/kg p.o.                            8      270   0.90    2 h after last appl.+                                    9      260   0.97                                                             10     280   0.83                                                             x.sub.10                                                                             235   0.88    p<0.001                                                  1      210   0.66    3-methylpyrazole-5-                                      2      190   0.59    carboxylic acid                                          3      220   0.53                                                             4      250   0.91    15 mg/kg p.o.                                            5      210   0.56    4 × appl.                                          6      210   0.95    30' after last                                           7      250   1.02    application +                                            8      220   0.81                                                             9      240   0.80                                                             10     210   0.60                                                             x.sub.10                                                                             221   0.74    p<0.001                                                  1      230   0.75    3-methylpyrazole-5-                                      2      220   0.73    carboxylic acid                                          3      210   0.95                                                             4      200   0.96    15 mg/kg p.o.                                            5      200   1.03    4 × appl.                                          6      230   1.16    1 h after last                                           7      190   1.08    application                                              8      210   0.84                                                             9      220   1.24                                                             10     240   0.92                                                             x.sub.10                                                                             215   0.97    p<0.001                                                  1      200   0.62    3-methylpyrazole-5-                                      2      220   0.59    carboxylic acid                                          3      230   0.51                                                             4      250   0.70    15 mg/kg p.o.                                            5      250   0.88    4 × appl.                                          6      270   0.84    2 h after last                                           7      220   1.27    application                                              8      230   1.20                                                             9      250   0.86                                                             x.sub.9                                                                              235   0.83    p<0.001                                                  __________________________________________________________________________

We claim:
 1. A 3-Methylpyrazole-5-carboxylate corresponding to thegeneral formula ##SPC3##in which R₁ and R₂ when taken separatelyrepresents hydrogen, a straight-chain or branched alkyl radical with 1to 5 carbon atoms, a hydroxyalkyl radical with 1 to 5 carbon atoms, analkoxyalkyl radical of 1 to 5 carbon atoms in each of the alkoxy andalkyl groups thereof, a phenylethyl group or norbornyl group or, R₁ andR₂, when taken together with the nitrogen atom to which they areattached, represent a morpholine radical.
 2. The compound according toclaim 1 wherein R₁ is methyl and R₂ is hydroxyethyl.
 3. A compositionfor treating a hyperlipacidaemic animal containing a compound of claim 1in a hyperlipacidaemic effective amount in combination with apharmacologically compatible carrier.